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The bone-forming effects of HIF-1α-transduced BMSCs promote osseointegration with dental implant in canine mandible.

Zou D, He J, Zhang K, Dai J, Zhang W, Wang S, Zhou J, Huang Y, Zhang Z, Jiang X - PLoS ONE (2012)

Bottom Line: HIF-1α mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction.Furthermore, osseointegration was significantly enhanced by HIF-1α-overexpressing canine BMSCs.This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1α in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.

View Article: PubMed Central - PubMed

Affiliation: Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.

ABSTRACT
The presence of insufficient bone volume remains a major clinical problem for dental implant placement to restore the oral function. Gene-transduced stem cells provide a promising approach for inducing bone regeneration and enhancing osseointegration in dental implants with tissue engineering technology. Our previous studies have demonstrated that the hypoxia-inducible factor-1α (HIF-1α) promotes osteogenesis in rat bone mesenchymal stem cells (BMSCs). In this study, the function of HIF-1α was validated for the first time in a preclinical large animal canine model in term of its ability to promote new bone formation in defects around implants as well as the osseointegration between tissue-engineered bone and dental implants. A lentiviral vector was constructed with the constitutively active form of HIF-1α (cHIF). The ectopic bone formation was evaluated in nude mice. The therapeutic potential of HIF-1α-overexpressing canine BMSCs in bone repair was evaluated in mesi-implant defects of immediate post-extraction implants in the canine mandible. HIF-1α mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction. Furthermore, osseointegration was significantly enhanced by HIF-1α-overexpressing canine BMSCs. This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1α in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.

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Histological analysis of newly formed bone and remnant scaffold area in calvarial defects.The specimens were sliced, and sections were stained with van Gieson's picrofuchsin. From top to bottom: Blank, CMPC construct, Lenti-GFP-transduced BMSCs/CMPC construct, Lenti-HIF-transduced BMSCs/CMPC construct, and Lenti-cHIF- transduced BMSCs/CMPC construct (F = fibroblastic-like tissue, C = CMPC, B = new bone, DI = dental implant; original magnification, 40×, 100×) (A). BIC per 40× field in histological sections (B). Bone density per 40× field in histological sections (C). The percentage of remnant scaffold area per 100× field in histological sections (D). (** P<0.01, target gene groups compared with the GFP group, Blank group or CMPC group).
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pone-0032355-g007: Histological analysis of newly formed bone and remnant scaffold area in calvarial defects.The specimens were sliced, and sections were stained with van Gieson's picrofuchsin. From top to bottom: Blank, CMPC construct, Lenti-GFP-transduced BMSCs/CMPC construct, Lenti-HIF-transduced BMSCs/CMPC construct, and Lenti-cHIF- transduced BMSCs/CMPC construct (F = fibroblastic-like tissue, C = CMPC, B = new bone, DI = dental implant; original magnification, 40×, 100×) (A). BIC per 40× field in histological sections (B). Bone density per 40× field in histological sections (C). The percentage of remnant scaffold area per 100× field in histological sections (D). (** P<0.01, target gene groups compared with the GFP group, Blank group or CMPC group).

Mentions: To further investigate the HIF-1α-mediated functional restoration of tissue-engineered bones in a large animal, we evaluated bone repair and osseointegration in canines using histologic and histomorphometric methods (Figure 7A). Under light microscopy, BIC was 91.24%±2.12% of the total area per 40× field in the cHIF group, 83.57%±2.33% in the HIF group, 62.94%±6.62% in the GFP group, 38.96%±4.87% in the CMPC group, and 40.06%±1.88% in the blank group. BIC in each target gene groups was significantly higher than the control groups (P<0.01), and no significant difference was observed between the CMPC group and the blank group (Figure 7B) (P>0.05). The newly formed bone showed varying degrees of bone density. Bone density was 46.82±4.64% of the total area per 40× field in the cHIF group, 40.02±1.82% in the HIF group, 20.06±5.12% in the GFP group, 12.37±2.31% in the CMPC group, and 16.76±5.24% in the blank group. There were significant differences in bone density between the cHIF or HIF group and each control group (P<0.01), but no significant difference was seen among the three control groups (Figure 7C). Furthermore, the percentage of remnant scaffold area was measured. These percentages were 22.16%±5.53%, 15.95%±1.87%, 12.25±6.42%, and 4.97%±2.26% of the total area per 100× field in the CMPC, GFP, HIF, and cHIF groups, respectively (Figure 7D).


The bone-forming effects of HIF-1α-transduced BMSCs promote osseointegration with dental implant in canine mandible.

Zou D, He J, Zhang K, Dai J, Zhang W, Wang S, Zhou J, Huang Y, Zhang Z, Jiang X - PLoS ONE (2012)

Histological analysis of newly formed bone and remnant scaffold area in calvarial defects.The specimens were sliced, and sections were stained with van Gieson's picrofuchsin. From top to bottom: Blank, CMPC construct, Lenti-GFP-transduced BMSCs/CMPC construct, Lenti-HIF-transduced BMSCs/CMPC construct, and Lenti-cHIF- transduced BMSCs/CMPC construct (F = fibroblastic-like tissue, C = CMPC, B = new bone, DI = dental implant; original magnification, 40×, 100×) (A). BIC per 40× field in histological sections (B). Bone density per 40× field in histological sections (C). The percentage of remnant scaffold area per 100× field in histological sections (D). (** P<0.01, target gene groups compared with the GFP group, Blank group or CMPC group).
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pone-0032355-g007: Histological analysis of newly formed bone and remnant scaffold area in calvarial defects.The specimens were sliced, and sections were stained with van Gieson's picrofuchsin. From top to bottom: Blank, CMPC construct, Lenti-GFP-transduced BMSCs/CMPC construct, Lenti-HIF-transduced BMSCs/CMPC construct, and Lenti-cHIF- transduced BMSCs/CMPC construct (F = fibroblastic-like tissue, C = CMPC, B = new bone, DI = dental implant; original magnification, 40×, 100×) (A). BIC per 40× field in histological sections (B). Bone density per 40× field in histological sections (C). The percentage of remnant scaffold area per 100× field in histological sections (D). (** P<0.01, target gene groups compared with the GFP group, Blank group or CMPC group).
Mentions: To further investigate the HIF-1α-mediated functional restoration of tissue-engineered bones in a large animal, we evaluated bone repair and osseointegration in canines using histologic and histomorphometric methods (Figure 7A). Under light microscopy, BIC was 91.24%±2.12% of the total area per 40× field in the cHIF group, 83.57%±2.33% in the HIF group, 62.94%±6.62% in the GFP group, 38.96%±4.87% in the CMPC group, and 40.06%±1.88% in the blank group. BIC in each target gene groups was significantly higher than the control groups (P<0.01), and no significant difference was observed between the CMPC group and the blank group (Figure 7B) (P>0.05). The newly formed bone showed varying degrees of bone density. Bone density was 46.82±4.64% of the total area per 40× field in the cHIF group, 40.02±1.82% in the HIF group, 20.06±5.12% in the GFP group, 12.37±2.31% in the CMPC group, and 16.76±5.24% in the blank group. There were significant differences in bone density between the cHIF or HIF group and each control group (P<0.01), but no significant difference was seen among the three control groups (Figure 7C). Furthermore, the percentage of remnant scaffold area was measured. These percentages were 22.16%±5.53%, 15.95%±1.87%, 12.25±6.42%, and 4.97%±2.26% of the total area per 100× field in the CMPC, GFP, HIF, and cHIF groups, respectively (Figure 7D).

Bottom Line: HIF-1α mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction.Furthermore, osseointegration was significantly enhanced by HIF-1α-overexpressing canine BMSCs.This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1α in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.

View Article: PubMed Central - PubMed

Affiliation: Ninth People's Hospital Affiliated with Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China.

ABSTRACT
The presence of insufficient bone volume remains a major clinical problem for dental implant placement to restore the oral function. Gene-transduced stem cells provide a promising approach for inducing bone regeneration and enhancing osseointegration in dental implants with tissue engineering technology. Our previous studies have demonstrated that the hypoxia-inducible factor-1α (HIF-1α) promotes osteogenesis in rat bone mesenchymal stem cells (BMSCs). In this study, the function of HIF-1α was validated for the first time in a preclinical large animal canine model in term of its ability to promote new bone formation in defects around implants as well as the osseointegration between tissue-engineered bone and dental implants. A lentiviral vector was constructed with the constitutively active form of HIF-1α (cHIF). The ectopic bone formation was evaluated in nude mice. The therapeutic potential of HIF-1α-overexpressing canine BMSCs in bone repair was evaluated in mesi-implant defects of immediate post-extraction implants in the canine mandible. HIF-1α mediated canine BMSCs significantly promoted new bone formation both subcutaneously and in mesi-implant defects, including increased bone volume, bone mineral density, trabecular thickness, and trabecular bone volume fraction. Furthermore, osseointegration was significantly enhanced by HIF-1α-overexpressing canine BMSCs. This study provides an important experimental evidence in a preclinical large animal model concerning to the potential applications of HIF-1α in promoting new bone formation as well as the osseointegration of immediate implantation for oral function restoration.

Show MeSH
Related in: MedlinePlus